Differential cell signaling testing for cell-cell communication inference from single-cell data by dominoSignal
Jacob T Mitchell1,2,3,4,5, Orian Stapleton1,2,3,4,6, Kavita Krishnan6,7
1Department of Oncology, Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
Biorxiv : the Preprint Server for Biology
|July 14, 2025
Summary
We developed dominoSignal, a new software tool to statistically identify differential cell signaling in single-cell data. This tool enables robust analysis of cell-cell communication changes across various biological conditions and experimental perturbations.
Area of Science:
- Computational Biology
- Single-cell Genomics
- Systems Biology
Background:
- Ligand-receptor network inference algorithms estimate cell-cell communication from single-cell data.
- Existing methods lack statistical approaches to identify significantly differential signaling between conditions.
- Previous work introduced Domino for cell communication inference based on gene expression and transcription factor activity.
Purpose of the Study:
- To develop dominoSignal software for statistically testing differential cellular signaling.
- To extend the functionality of the Domino algorithm for comparative analyses.
- To provide a robust method for analyzing cell-cell communication in multi-subject single-cell datasets.
Main Methods:
- Developed the dominoSignal software incorporating statistical testing for differential signaling.
- Implemented functionality for compiling active signals across multiple subjects and testing condition-dependent linkages.
- Utilized simulation studies to benchmark the required number of subjects and cells for accurate differential linkage identification.
Main Results:
- The dominoSignal software enables statistically rigorous comparison of cell-cell communication networks.
- Simulation studies provide guidelines for sample size and cell type annotation needed for reliable differential analysis.
- Demonstrated application of the Differential Cell Signaling Test (DCST) in cancer studies.
Conclusions:
- dominoSignal provides a powerful new capability for inferring changes in cell communication networks.
- The Differential Cell Signaling Test (DCST) can reveal effects of cancer phenotypes and immunotherapy on tumor microenvironment communication.
- This approach is broadly applicable for analyzing perturbations across diverse biological systems.
Related Concept Videos
01:21Cell-surface Signaling
Hormones—or any molecule that binds to a receptor, known as a ligand—that are lipid-insoluble (water-soluble) are not able to diffuse across the cell membrane. In order to be able to affect a cell without entering it, these hormones bind to receptors on the cell membrane. When a first messenger, a hormone, binds to a receptor, a signal cascade is set off, causing second messengers, proteins inside the cell, to become activated, resulting in downstream effects.
02:03What is Cell Signaling?
Despite the protective membrane that separates a cell from the environment, cells need the ability to detect and respond to environmental changes. Additionally, cells often need to communicate with one another. Unicellular and multicellular organisms use a variety of cell signaling mechanisms to communicate to respond to the environment.
02:03What is Cell Signaling?
Despite the protective membrane that separates a cell from the environment, cells need the ability to detect and respond to environmental changes. Additionally, cells often need to communicate with one another. Unicellular and multicellular organisms use a variety of cell signaling mechanisms to communicate to respond to the environment.
01:23Overview of Cell Signaling
Despite the protective membrane that separates a cell from the environment, cells need the ability to detect and respond to environmental changes. Additionally, cells often need to communicate with one another. Unicellular and multicellular organisms use a variety of cell signaling mechanisms to communicate with the environment.
Cells respond to many types of information, often through receptor proteins positioned on the membrane. For example, skin cells respond to and transmit touch...
Cells respond to many types of information, often through receptor proteins positioned on the membrane. For example, skin cells respond to and transmit touch...
01:22Diversity in Cell Signaling Responses
The physiological function of a cell and cellular communication are outcomes of a range of extrinsic signals, intracellular signaling pathways, and cellular responses. No two cell types express the same repertoire of signaling components. Receptors are highly selective for their cognate ligands, but once activated, they can alter multiple cellular processes such as DNA transcription, protein synthesis, and metabolic activity.
Graded and Abrupt Responses
Some signaling systems generate...
Graded and Abrupt Responses
Some signaling systems generate...
01:23Overview of Cell Signaling
Despite the protective membrane that separates a cell from the environment, cells need the ability to detect and respond to environmental changes. Additionally, cells often need to communicate with one another. Unicellular and multicellular organisms use a variety of cell signaling mechanisms to communicate with the environment.
Cells respond to many types of information, often through receptor proteins positioned on the membrane. For example, skin cells respond to and transmit touch...
Cells respond to many types of information, often through receptor proteins positioned on the membrane. For example, skin cells respond to and transmit touch...